Alzheimer's disease (AD) is associated with a build up of oxidative stress in addition to the classic neuropathological signs of amyloid plaques, neurofibrillary tangles and cell death. An adequate supply of antioxidants in the diet during the lifetime, and especially in at-risk populations may mitigate the risk of excess damage by oxidative stress, however, the exact roles of particular antioxidants have yet to be clarified. In the current application we propose to investigate the role of vitamin C (ascorbic acid; ASC) in the development of neuropathology and cognitive deficits in a mouse model of AD. Further we will investigate the therapeutic potential of ASC to treat memory impairments. ASC is transported across the choroid plexus and into neurons by the Sodium-dependent Vitamin C Transporter (SVCT2). The creation of new mouse lines that either lack, or carry additional copies of the SVCT2 permits us for the first time to investigate the effects of a long term decrease or increase in brain ASC level, by the same mechanism, and without risk of ill health due to scurvy. We will cross these mice with an established mouse model of AD, APP/PSEN1 mice, and investigate how differing ASC levels impact the development of learning and memory impairments and also concomitant neuropathological changes at early, mid-, and later stages of disease progression. We anticipate that these data will reinforce the necessity to promote adequate intake of ASC and other antioxidants throughout the life-span, but especially in at-risk individuals. More importantly the data will tell us how ASC interacts with disease pathology to offer this critical neuroprotection. Finally, we present evidence that ASC can act as a neuromodulator, and we propose to investigate the potential of ASC to act as a novel, acute treatment via interperitoneal, and intra-ventricular treatments. These data will provide evidence that ASC can be used as a non-toxic treatment to improve memory deficits in APP/PSEN1 mice, and to promote further investigation of their use in humans. PUBLIC HEALTH RELEVANCE: This project is to study the relationship between vitamin C and oxidative stress in the aging brain and in Alzheimer's disease. It will provide clear evidence as to the role of vitamin C in Alzheimer neuropathology and associated learning and memory deficits. It will also investigate the potential for vitamin C administration via parenteral routes, as a new therapeutic strategy.